Background: Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to cancer. The group has developed genotyping assays for the "at-risk" variants of enzymes that protect against carcinogens in cigarette smoke, diet, industrial processes and environmental pollution. Following genotyping of over 15,000 individuals for these candidate susceptibility genes, it has been found that the frequency of the at-risk genotypes for glutathione transferase M1 (GSTM1), theta 1 (GSTT1), Pi (GSTP1) and N-acetyltransferase (NAT1 and NAT2) vary significantly between Asians, European- and African-Americans. This suggests that some of the ethnic differences in cancer incidence may be due to genetic metabolic differences as well as exposure differences.Aims: In ongoing studies with researchers at the NIEHS, National Cancer Institute, Columbia Univ., Johns Hopkins Univ., Univ. of North Carolina and Univ. of Occupational and Environmental Health, Japan, the Genetic Risk Group (GRG) is testing the impact of these cancer susceptibility genes in case-control studies of cancer of the bladder, skin, lung, liver, colon, stomach, prostate, and breast. Accomplishments: We have tested for a role for polymorphism in CYP17 and SRD5A2 in prostate cancer and observe little effect (10). We failed to detect any association between organochlorine compounds and risk of breast cancer (8). We find that GSTM1 and T1 polymorphisms may influence risk of atherosclerosis among smokers (11) but these polymorphisms have little affect in breast cancer (14). It was found that genetic factors (CYP1A1 and GSTP1 polymorphisms) modulate levels of DNA damage in placenta and fetal cord blood (7).NAT1 and NAT2 were found to play a role in the development of gastric cancer (15). We have modeled how glutathione transferase T1 polymorphism may impact risk estimates for dichloromethane exposure (16).Significance: These studies seek to integrate environmental and genetic factors into our understanding of the etiology of human disease.